2-55667112-T-C

Variant names:

• chr2-55667112-T-C
• rs782637
• NM_033109.5:c.1074-19A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033109.5(PNPT1):​c.1074-19A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 1,570,290 control chromosomes in the GnomAD database, including 189,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.44 (15891 hom., cov: 32)
  • Exomes 𝑓: 0.49 (173284 hom.)
• Consequence: PNPT1 NM_033109.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.247
• Publications: 14 publications found

Genes affected

PNPT1 (HGNC:23166): (polyribonucleotide nucleotidyltransferase 1) The protein encoded by this gene belongs to the evolutionary conserved polynucleotide phosphorylase family comprised of phosphate dependent 3'-to-5' exoribonucleases implicated in RNA processing and degradation. This enzyme is predominantly localized in the mitochondrial intermembrane space and is involved in import of RNA to mitochondria. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency-13 and autosomal recessive nonsyndromic deafness-70. Related pseudogenes are found on chromosomes 3 and 7. [provided by RefSeq, Dec 2012]

PNPT1 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation defect type 13

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hearing loss disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• spinocerebellar ataxia type 25

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• autosomal recessive nonsyndromic hearing loss 70

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-55667112-T-C is Benign according to our data. Variant chr2-55667112-T-C is described in ClinVar as Benign. ClinVar VariationId is 138735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPT1	NM_033109.5	c.1074-19A>G		intron_variant	Intron 12 of 27	ENST00000447944.7	NP_149100.2
PNPT1	XM_005264629.3	c.834-19A>G		intron_variant	Intron 12 of 27		XP_005264686.1
PNPT1	XM_017005172.2	c.834-19A>G		intron_variant	Intron 11 of 26		XP_016860661.1
PNPT1	XM_047446161.1	c.1074-19A>G		intron_variant	Intron 12 of 19		XP_047302117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPT1	ENST00000447944.7	c.1074-19A>G		intron_variant	Intron 12 of 27	1	NM_033109.5	ENSP00000400646.2
PNPT1	ENST00000260604.8	n.*629-19A>G		intron_variant	Intron 11 of 26	5		ENSP00000260604.4
PNPT1	ENST00000415374.5	n.1074-19A>G		intron_variant	Intron 12 of 28	5		ENSP00000393953.1
PNPT1	ENST00000415489.1	n.147-19A>G		intron_variant	Intron 2 of 7	3		ENSP00000411057.1

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67525 AN: 151930 Hom.: 15896 Cov.: 32

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.477

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.577

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.471

GnomAD2 exomes AF: 0.440 AC: 108601 AN: 246766 AF XY: 0.438

Gnomad AFR exome AF: 0.314

Gnomad AMR exome AF: 0.435

Gnomad ASJ exome AF: 0.483

Gnomad EAS exome AF: 0.152

Gnomad FIN exome AF: 0.578

Gnomad NFE exome AF: 0.520

Gnomad OTH exome AF: 0.488

GnomAD4 exome AF: 0.486 AC: 689819 AN: 1418242 Hom.: 173284 Cov.: 24 AF XY: 0.481 AC XY: 340393 AN XY: 708056

African (AFR) AF: 0.315 AC: 10151 AN: 32214

American (AMR) AF: 0.446 AC: 19599 AN: 43904

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 12349 AN: 25686

East Asian (EAS) AF: 0.165 AC: 6477 AN: 39272

South Asian (SAS) AF: 0.271 AC: 22933 AN: 84672

European-Finnish (FIN) AF: 0.575 AC: 30594 AN: 53234

Middle Eastern (MID) AF: 0.443 AC: 2509 AN: 5670

European-Non Finnish (NFE) AF: 0.519 AC: 557550 AN: 1074718

Other (OTH) AF: 0.470 AC: 27657 AN: 58872

GnomAD4 genome AF: 0.444 AC: 67539 AN: 152048 Hom.: 15891 Cov.: 32 AF XY: 0.442 AC XY: 32870 AN XY: 74336

African (AFR) AF: 0.321 AC: 13314 AN: 41492

American (AMR) AF: 0.495 AC: 7553 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 1655 AN: 3470

East Asian (EAS) AF: 0.159 AC: 823 AN: 5174

South Asian (SAS) AF: 0.261 AC: 1259 AN: 4816

European-Finnish (FIN) AF: 0.577 AC: 6093 AN: 10564

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.521 AC: 35423 AN: 67964

Other (OTH) AF: 0.468 AC: 985 AN: 2106

Alfa AF: 0.452 Hom.: 11847

Bravo AF: 0.433

Asia WGS AF: 0.248 AC: 864 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

May 21, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Combined oxidative phosphorylation defect type 13 Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 70 Benign:1

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.14
DANN	Benign	0.62
PhyloP100		-0.25
BranchPoint Hunter		4.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs782637; hg19: chr2-55894247; COSMIC: COSV53179089;